| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 50mg | |||
| Other Sizes |
Purity: ≥98%
| Targets |
Caspase-1 (interleukin-1β converting enzyme / ICE). Caspase-1 is a cysteine protease that cleaves pro-IL-1β and pro-IL-18 into their active inflammatory cytokines. By inhibiting caspase-1, Pralnacasan reduces the production of mature IL-1β and IL-18, thereby attenuating the inflammatory cascade. The compound has a Ki of 1.4 nM and shows selectivity over apoptotic caspases-3 and -8.
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| ln Vitro |
In vitro, Pralnacasan demonstrates potent caspase-1 inhibitory activity with an IC50 of 1.3-3.6 nM. It shows selectivity for caspase-1 over apoptotic caspases-3 and -8. The compound's prodrug form (RU36384/VRT-18858) also exhibits potent in vitro activity. Pralnacasan inhibits IL-1β production in cell-based assays, confirming its mechanism of action as a caspase-1 inhibitor.
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| ln Vivo |
Joint injury was lessened by pralnacasan (0–50 mg/kg; oral gavage; twice daily; for 6 weeks; female Balb/c mice). Animal body weight does not seem to be impacted by pranacadasan therapy [1].
In vivo, Pralnacasan reduces joint damage in two murine models of osteoarthritis. The compound is orally active and has been evaluated in preclinical models of inflammatory diseases. Its ability to inhibit caspase-1 in vivo results in reduced IL-1β and IL-18 levels, leading to decreased inflammation and tissue damage. The compound's efficacy in osteoarthritis models supported its progression into clinical development. |
| Enzyme Assay |
Cell-free enzyme assays for Pralnacasan use recombinant human caspase-1 and a fluorogenic substrate (e.g., Ac-YVAD-AMC). The compound is incubated with the enzyme at varying concentrations (0.01-10000 nM) for 30-60 minutes at 37°C. Substrate cleavage is monitored by fluorescence at excitation/emission wavelengths of 360/460 nm. IC50 and Ki values are calculated from dose-response curves. Selectivity profiling is performed against other caspases (caspase-3, -8) using the same assay format.
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| Cell Assay |
Cellular assays for Pralnacasan use human peripheral blood mononuclear cells (PBMCs) or THP-1 monocytes stimulated with LPS to induce IL-1β production. Cells are pre-incubated with Pralnacasan at concentrations ranging from 0.01-100 μM for 1-2 hours, then stimulated with LPS for 4-24 hours. IL-1β levels in culture supernatants are measured by ELISA. Inhibition of IL-1β production is calculated and IC50 values are determined. Cytotoxicity is assessed using LDH release or MTT assays to ensure that observed effects are not due to cell death.
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| Animal Protocol |
Animal/Disease Models: Collagenase-induced female balb/c (Bagg ALBino) mouse [1]
Doses: 0 mg/kg, 12.5 mg/kg, 25 mg/kg and 50 mg/kg Route of Administration: po (oral gavage); twice a day; continuous 6-week Experimental Results: Histopathological lesions in the medial compartment of the knee improved Dramatically. In vivo efficacy studies are conducted in murine models of osteoarthritis or other inflammatory diseases. Pralnacasan is administered orally at doses typically ranging from 1-30 mg/kg, daily or twice daily. Disease progression is monitored by histopathological assessment of joint tissue, measurement of inflammatory cytokine levels in serum or joint fluid, and behavioral assessment of pain or mobility. Pharmacodynamic studies involve measuring IL-1β and IL-18 levels in plasma or tissue to confirm target engagement. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Oral Bioavailability Pharmacokinetic studies of Pralnacasan in preclinical species demonstrate that the compound is orally bioavailable. Its prodrug form (RU36384/VRT-18858) was designed to improve oral absorption. The compound is metabolized to its active form and distributes to target tissues. PK parameters such as Cmax, Tmax, AUC, half-life, and bioavailability are determined in rodents and non-human primates. The compound's oral bioavailability supports its use in chronic dosing regimens for inflammatory diseases. |
| Toxicity/Toxicokinetics |
Toxicology studies of Pralnacasan were conducted as part of its clinical development program. As a caspase-1 inhibitor, potential toxicities are related to its mechanism of action, including effects on the immune system and potential for increased susceptibility to infections. Standard toxicology studies (acute, subchronic, and chronic) were performed in rodents and non-human primates. The compound's safety profile was evaluated in clinical trials for osteoarthritis. Specific toxicity findings are not widely reported in public sources.
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| References |
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| Additional Infomation |
Pralnacasan is an orally bioavailable prodrug whose active ingredient is a potent non-peptide interleukin-1β converting enzyme (ICE) inhibitor. Indications: For the treatment of rheumatoid arthritis (RA). Mechanism of Action: Pralnacasan inhibits interleukin-1β converting enzyme (ICE), an enzyme that regulates the production of IL-1 and IFN-γ—intercellular mediators that initiate and maintain inflammatory processes. Inhibition of ICE may be an effective strategy to reduce the harmful inflammatory processes common in many acute and chronic diseases, such as rheumatoid arthritis (RA) and osteoarthritis. Pharmacodynamics: Pralnacasan is a potent non-peptide interleukin-1β converting enzyme (ICE) inhibitor. Pralnacasan is an oral anti-cytokine candidate drug, licensed for development by Aventis Pharma from Vertex Pharmaceuticals. In November 2003, Aventis and Vertex Pharmaceuticals announced that they were voluntarily pausing their Phase II clinical trial of Pralnacasan due to liver abnormalities observed in animals after nine months of treatment with high doses of the drug in an animal toxicity study. Although similar hepatotoxicity had not been observed in human trials to date, the two companies would evaluate the animal toxicity study results before proceeding with the Phase II clinical trial.
Pralnacasan (VX-740) was a clinical-stage drug candidate for the treatment of osteoarthritis and other inflammatory diseases. It was developed by Vertex Pharmaceuticals and progressed into clinical trials, but development was ultimately discontinued. The compound represents an important example of a caspase-1 inhibitor that reached clinical testing. Its development contributed to the understanding of the role of the inflammasome and IL-1β in inflammatory diseases. The compound is available for research purposes. |
| Molecular Formula |
C26H29N5O7
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|---|---|
| Molecular Weight |
523.53776
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| Exact Mass |
523.207
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| CAS # |
192755-52-5
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| PubChem CID |
153270
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| Appearance |
White to off-white solid powder
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| Density |
1.44g/cm3
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| Index of Refraction |
1.657
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| LogP |
1.762
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
|
| Rotatable Bond Count |
6
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| Heavy Atom Count |
38
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| Complexity |
960
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| Defined Atom Stereocenter Count |
4
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| SMILES |
CCO[C@H]1[C@H](CC(=O)O1)NC(=O)[C@@H]2CCCN3N2C(=O)[C@H](CCC3=O)NC(=O)C4=NC=CC5=CC=CC=C54
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| InChi Key |
CXAGHAZMQSCAKJ-WAHHBDPQSA-N
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| InChi Code |
InChI=1S/C26H29N5O7/c1-2-37-26-18(14-21(33)38-26)29-23(34)19-8-5-13-30-20(32)10-9-17(25(36)31(19)30)28-24(35)22-16-7-4-3-6-15(16)11-12-27-22/h3-4,6-7,11-12,17-19,26H,2,5,8-10,13-14H2,1H3,(H,28,35)(H,29,34)/t17-,18-,19-,26+/m0/s1
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| Chemical Name |
(1S,9S)-N-((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)-9-(isoquinoline-1-carboxamido)-6,10-dioxooctahydro-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxamide
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| Synonyms |
VX740 HMR 3480 VX 740 HMR-3480 VX-740 HMR3480
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~220 mg/mL (~420.22 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5.5 mg/mL (10.51 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 55.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 5.5 mg/mL (10.51 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 55.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 5.5 mg/mL (10.51 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9101 mL | 9.5504 mL | 19.1007 mL | |
| 5 mM | 0.3820 mL | 1.9101 mL | 3.8201 mL | |
| 10 mM | 0.1910 mL | 0.9550 mL | 1.9101 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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